Spinal Muscular Atrophy and Hereditary Motor Neuropathies
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Direct answer
Spinal muscular atrophy is an autosomal recessive lower motor neuron disease caused by homozygous deletion of the SMN1 gene in about 95 per cent of patients. It produces symmetrical proximal weakness, areflexia and fasciculations, with severity largely set by the number of SMN2 copies. Hereditary neuropathies, such as distal hereditary motor neuropathy and Charcot-Marie-Tooth disease, differ mainly in their distal pattern and sensory involvement.
What you must remember
- Genetics: SMN1 homozygous deletion in about 95 per cent of cases, with SMN2 copy number modifying severity.
- Clinical types: type 1 presents before six months and never sits unsupported, type 2 sits but never walks, type 3 walks, and type 4 begins in adulthood.
- Lower motor neuron pattern: proximal weakness, hypotonia, areflexia and fasciculations, with no sensory loss and no Babinski sign.
- Respiratory involvement: intercostal weakness causes paradoxical breathing and a bell-shaped chest in severe type 1 disease.
- Disease-modifying therapy: intrathecal nusinersen, oral risdiplam and intravenous onasemnogene abeparvovec gene therapy, with availability varying by country.
- CMT1A: a PMP22 duplication on chromosome 17p12 causes the commonest form of Charcot-Marie-Tooth disease, with markedly slowed conduction.
- Diagnostic test: SMN1 deletion analysis confirms spinal muscular atrophy, while nerve conduction studies separate it from neuropathy.
Localising weakness to the anterior horn cell
A 2-year-old girl cannot sit unsupported, has a tongue with fasciculations and absent knee jerks. She also breathes with a paradoxical abdominal movement when tired. The findings localise the lesion to the anterior horn cell, and the table compares the main alternatives.
| Feature | Spinal muscular atrophy | Distal hereditary motor neuropathy | CMT1A |
|---|---|---|---|
| Gene | SMN1 deletion | Several genes, including BSCL2 | PMP22 duplication |
| Weakness pattern | Proximal, symmetrical | Distal, hand wasting | Distal, with foot drop |
| Sensory loss | Absent | Absent or mild | Present |
| Nerve conduction | Reduced motor responses, normal sensory | Motor changes, normal sensory | Markedly slowed velocities |
Sensory loss with pes cavus and hammer toes points away from spinal muscular atrophy towards CMT. Nerve conduction testing settles the question, since spinal muscular atrophy preserves sensory responses while CMT slows conduction across both sensory and motor fibres.
Management of an infant starts with respiratory and nutritional support, because weak intercostal muscles and bulbar involvement threaten breathing and swallowing. Genetic confirmation then guides counselling for the family and early access to disease-modifying treatment, where it is available.
Where the exam tries to catch you
Most errors come from calling a floppy child a neuropathy or confusing the dystrophy and atrophy genes.
- Trap: calling spinal muscular atrophy a neuropathy because of areflexia Correct: it is an anterior horn cell disease, so sensory responses are typically preserved.
- Trap: using SMN2 copy number to make the diagnosis Correct: SMN1 deletion diagnoses the disease, while SMN2 copies predict severity.
- Trap: attributing spinal muscular atrophy to dystrophin Correct: dystrophin defects cause dystrophinopathies, a myopathy, whereas SMA involves SMN1 and the motor neuron.
Frequently asked questions
Which gene is deleted in spinal muscular atrophy?
Spinal muscular atrophy is caused by homozygous deletion of the SMN1 gene in about 95 per cent of patients. The remaining patients carry a SMN1 mutation over a deletion on the other allele. Disease severity is modified by the copy number of the nearly identical SMN2 gene.
Why does SMN2 copy number determine severity in spinal muscular atrophy?
SMN2 copy number determines severity because SMN2 produces only a small proportion of functional SMN protein, and more copies raise the total amount. Patients with few copies typically have type 1 disease, while those with more copies often walk. This is why copy number predicts prognosis.
Which features separate spinal muscular atrophy from hereditary motor neuropathy?
Spinal muscular atrophy shows fasciculations, areflexia and motor weakness without sensory loss, reflecting anterior horn cell degeneration. Hereditary motor neuropathies often show distal weakness and wasting, and some types involve sensory nerves and pes cavus. Nerve conduction studies help confirm the level of the lesion.
What does the CMT1A mutation involve?
CMT1A is caused by a duplication of the PMP22 gene on chromosome 17p12, and it is the commonest form of Charcot-Marie-Tooth disease. It is demyelinating, with markedly slowed nerve conduction velocities. Distal weakness, sensory loss, pes cavus and hammer toes are typical features.
How do disease-modifying treatments work in spinal muscular atrophy?
Nusinersen, risdiplam and onasemnogene abeparvovec are disease-modifying treatments that increase functional SMN protein. Nusinersen is given intrathecally, risdiplam is an oral modifier of SMN2 splicing, and onasemnogene abeparvovec delivers a functional SMN1 gene. Availability and funding vary by country, so early diagnosis matters.